Esophageal Submucosal Injection of Capsaicin but Not Acid Induces Symptoms in Normal Subjects

Abstract

Background/AimsTransient receptor potential vanilloid-1 (TRPV1) is a candidate for mediating acid-induced symptoms in the esophagus. We conducted studies to determine if the presence of acid in the mucosa/submucosa and direct activation of TRPV1 by capsaicin elicited symptoms in normal healthy subjects. We also studied the presence of TRPV1 receptors in the esophagus. MethodsUnsedated endoscopy was performed on healthy subjects with no symptoms. Using a sclerotherapy needle, normal saline (pH 2.0-7.5) was injected into the mucosa/submucosa, 5 cm above the Z line. In a separate group of healthy subjects, injection of capsaicin and vehicle was also studied. Quality of symptoms was reported using the McGill Pain Questionnaire, and symptom intensity using the visual analogue scale (VAS). Immunohistochemistry was performed on 8 surgical esophagus specimens using TRPV1 antibody. ResultsAcid injection either did not elicit or elicited mild symptoms in subjects at all pH solutions. Capsaicin but not the vehicle elicited severe heartburn/chest pain in all subjects. Mean VAS for capsaicin was 91 ± 3 and symptoms lasted for 25 ± 1 minutes. Immunohistochemistry revealed a linear TRPV1 staining pattern between the epithelial layer and the submucosa that extended into the papillae. Eighty-five percent of papillae stained positive for TRPV1 with a mean 1.1 positive papillae per high-powered field. ConclusionsThe mechanism of acid-induced heartburn and chest pain is not the simple interaction of hydrogen ions with afferents located in the esophageal mucosa and submucosa. TRPV1 receptors are present in the lamina propria and their activation induces heartburn and chest pain.

The Potential Role for Impaired Mucosal Integrity in the Generation of Esophageal Pain Using Capsaicin in Humans: An Explorative Study

“…Although protons also mainly activate the TRPV1 ion channel similar to the selective agonist capsaicin, the binding sites and the activation mechanisms are different ( 31 ). Furthermore, acid perfusion elicited almost no symptoms ( 17 ) in agreement with the observation that esophageal submucosal injection of capsaicin but not acid was able to induce pain ( 32 ). Therefore, we hypothesize that the reflectory reinforcement of the mucosal barrier, in particular in the proximal esophagus, is specifically induced when pain signals are generated.…”

QX‐314 inhibits acid‐induced activation of esophageal nociceptive C fiber neurons

“…Previous clinical studies have revealed that esophageal nociceptive symptoms, such as heartburn, are correlated well with the increased density of TRPV1‐positive nerve fibers in esophageal mucosa . Recent clinical studies demonstrated that direct instillation or submucosal injection of capsaicin in the esophagus produced esophageal nociceptive symptoms such as heartburn in healthy subjects . These clinical findings indicated that TRPV1 plays a crucial role in acid‐evoked activation of esophageal nociceptors.…”

“…23 Recent clinical studies demonstrated that direct instillation or submucosal injection of capsaicin in the esophagus produced esophageal nociceptive symptoms such as heartburn in healthy subjects. 24,25 These clinical findings indicated that TRPV1 plays a crucial role in acid-evoked activation of esophageal nociceptors. Recent studies from ours and others have demonstrated that esophageal nociceptors are usually TRPV1-positive afferent C fibers, and acid selectively activates esophageal nociceptive neural crest vagal jugular (and DRG) C fiber subtypes through TRPV1-mediated mechanism.…”

Gastroesophageal Reflux Disease: Pathophysiology and New Treatment Trends

“…Symptom intensity was investigated using a visual analog scale. The symptoms appeared only when capsaicin was injected and did not appear when acids with a pH of 2 were injected ( 9 ). These findings suggest that the cause of the symptoms is not the direct stimulus of acid but rather perceptual stimuli mediated by TRPV1.…”